The overarching objective of this research program is to invent and develop efficient chemical synthesis methods that allow complex polyfunctional molecules to be prepared as single enantiomers in practical fashion. We target structural motifs that are commonly found in molecules of biomedical relevance, yet are difficult, or impossible, to prepare with existing chemical methods. One emphasis of the proposed research is the development of practical chemistry for the asymmetric synthesis of two heterocyclic motifs that are found in numerous biologically active natural products, epidithiodioxopiperazines and tertiary carbinyl heterocyclic amines. The proposed studies will also continue our development of versatile methods for constructing complex polyfunctional molecules containing quaternary carbon stereocenters. The new chemical synthesis methods we develop will be evaluated in the context of the enantioselective total synthesis of structurally complex, biologically active alkaloids, for which no chemical synthesis entry exists. Our total synthesis targets include (a) alkaloids that contain an epidithiodioxopiperazine ring fused to a cyclotryptamine fragment, such as bionectin A, gliocladine A, leptosin D, and verticillin A, (b) the kapakahine alkaloids A and F, and (c) communensin A. We will collaborate in studies to confirm and evaluate the antimalarial properties of kapakahine alkaloids and in broad phenotypic screening of the novel structures prepared in this program of research. In the long term, the availability of the new organic synthesis methods that are developed in this research will facilitate discovery and production of improved drugs for treating medical disorders. PUBLIC HEALTH RELEVANCE The aim of the proposed research is to develop new chemical transformations that allow biologically active organic molecules to be prepared from inexpensive starting materials by chemical synthesis. This new chemistry will be of value in the discovery and production of new medicines, as well as in molecular-level studies of life processes.